AP
Ischemic heart disease remains the leading cause of death worldwide, with myocardial infarction (MI), commonly known as a heart attack, being a significant initial event. This occurs when insufficient blood flow to the coronary arteries leads to the death of heart tissue, often resulting in heart failure, heart wall remodeling, and severe inflammation. Despite these severe outcomes, current anti-inflammatory medications have been largely ineffective in preventing heart failure after a heart attack, and thus are not routinely included in post-MI treatment plans. The underlying cellular and molecular triggers of this inflammation have remained elusive—until now.
In the August 28, 2024 issue of Nature, a research team from the University of California San Diego, led by Dr. Kevin King, has uncovered a novel mechanism of cardiac inflammation that may pave the way for new therapies to prevent heart attacks from progressing to heart failure.
Traditionally, inflammation following an MI has been attributed to immune cells like neutrophils and macrophages that flood the damaged heart tissue, responding to signals from dying cells. However, Dr. King and his colleagues made a surprising discovery: the pro-inflammatory "type I interferon (IFN) response" was not activated in the infarcted area itself, where immune cells are concentrated, but rather in the surrounding borderzone. The borderzone is a critical yet understudied area of the heart, where surviving heart muscle cells strive to stabilize and even regenerate after being severed from their neighboring dying cells.
Studying the borderzone has historically been challenging due to its complex integration with the rest of the heart. However, the research team overcame this hurdle by employing advanced techniques like single-cell RNA sequencing and spatial transcriptomics, which allowed them to identify the distinct gene expression patterns of cells in the borderzone. To pinpoint the exact cell type responsible for initiating borderzone inflammation, the team engineered a library of conditional knockout mice, each deficient in IFN signaling in a specific cell type.
The results were unexpected: heart muscle cells, or cardiomyocytes, emerged as the primary instigators of IFN signaling in the borderzone. The researchers found that these cardiomyocytes, under mechanical stress, often suffered nuclear envelope rupture, allowing nuclear DNA to escape into the cytoplasm. This triggered cytosolic DNA sensors, activating IFN signaling and leading to the mechanical weakening of the heart wall. This process increases the risk of heart wall dilation, thinning, and rupture, offering a possible explanation for the improved survival rates in mice lacking IFN responses, as observed in the team’s earlier studies.
Dr. King, a senior author of the study and a faculty member at UC San Diego's Shu Chien Gene Lay Department of Bioengineering and the Division of Cardiology, emphasized the importance of these findings. "In the hospital, we care for patients with heart attacks and heart failure every day. Identifying new therapeutic targets for MI that could prevent the development of heart failure is incredibly important," he said. While many questions remain, the research suggests that targeting mechanical stress in the borderzone, inhibiting DNA sensing, and blocking type I IFN signaling could provide new strategies to help patients avoid heart failure after a heart attack.
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